DESCRIPTION: Diseases of neurodegeneration and brain damage from non-missile head trauma account for nearly 500,000 hospital admissions in the U.S. annually. Although the etiology may differ, the same anatomic and physiologic substrates are involved in these conditions, including ischemia and hypoxic injury and the release of excitatory amino acids, especially glutamate from diseased or damaged cells. We have been using in vitro and in vivo models of experimental ischemia and cellular models of glutamate toxicity to examine these mechanisms of neuronal injury, and to target early intervention treatment strategies for neurodegeneration. One promising strategy that has not been explored is the use of low doses of chemicals to enhance cell tolerance and recovery. High doses of toxic chemicals will inhibit and kill biological systems, while low doses frequently stimulate those systems. Stimulation of cell function by exposure to low doses of chemicals can often mitigate the adverse effects produced by high doses. This phenomenon is the theoretical basis for the observed effects in homeopathy. While paradoxical dose effects been demonstrated across multiple cells types and phyla they have not yet been examined in neurodegeneration. In preliminary research we have demonstrated that protective effects occur in neuronal cells exposed to low and ultra-low doses of glutamate and that ultra-low dose glutamate and homeopathic Arnica montana can significantly reduce brain damage from ischemia in vivo. The objective of this project is to use neuronal culture systems and ischemia models of brain injury to identify the optimal protective doses and routes of glutamate and homeopathic Arnica montana exposure. Once these dosages are identified we will examine the in vivo effects of these preparations to target mechanism and clinical studies in the future. We will have developed, for the first time, a systematic model for the scientific study of protective hormesis and homeopathy in neurodegeneration and brain injury.